The aberrant vascular morphology, spatial heterogeneity in vessels, and metabolic microenvironments associated with solid tumors, are major factors contributing to treatment failures in radiotherapy. Since all of these may be affected by treatment with vascular targeting agents (VTAs), the combination of such agents with radiotherapy is likely to improve treatment outcomes. Indeed, we previously have shown that combining a VTA with radiotherapy would allow the two treatments to act in a complimentary fashion in tumors at the microregional level resulting in an overall amplification of the antitumor effects of radiation. Though clearly promising, many questions regarding the successful application of this new approach to cancer treatment remain. The central goal of the present application is to develop new insights into the underlying mechanisms of vascular targeting therapy and to explore new avenues to maximize its therapeutic potential. One of the issues to be addressed in this research program is whether at lower doses than have typically be used pre-clinically, but closer to those attainable in the clinic, enhancement of radiation response by VTAs is still feasible. Secondly, we propose to examine whether post VTA treatment conditions provide a favorable setting for the application of antiangiogenic therapies. This strategy is based on the observation that cells surviving VTA treatment at the tumor periphery aggressively promote neovascularization in order to achieve the rapid regrowth that occurs from the viable rim. A third component of the program is focused on the evaluation of new emerging second generation compounds as current VTAs progress through early clinical trial evaluations. Specifically the antitumor potency and potential superiority of a recently identified lead candidate analog of combretastatin will be examined. Finally, based on the hypothesis that targeting the tumor neovasculature should offer the possibility of inducing responses in all tumors with an established vessel network, we will examine whether in addition to their activity in primary tumors, VTAs can impact the management of metastatic disease. [unreadable] [unreadable]